2-(6-Methoxynaphth-2-yl) propionitrile

ABSTRACT

New compounds, 2-(6&#39;&#39;-methoxynaphth-2&#39;&#39;-yl)propylene oxide, 2-(6&#39;&#39;methoxynaphth-2&#39;&#39;-yl)propionaldoximo, 2-hydroxy-2-(6&#39;&#39;methoxynaphth-2&#39;&#39;-yl)propionitrile, 2-(6&#39;&#39;-methoxynaphth-2&#39;&#39;yl)acrylonitrile, 2-(6&#39;&#39;-methoxynaphth-2&#39;&#39;-yl)acrylic acid, the corresponding 5&#39;&#39;-halo compounds and 2-(5&#39;&#39;-halo-6&#39;&#39;-methoxynaphth2&#39;&#39;-yl)propionaldehyde are useful intermediates in producing 2(6&#39;&#39;-methoxynaphth-2&#39;&#39;-yl)propionic acid and the corresponding 5&#39;&#39;halo acids from 6-methoxy-2-acetylnaphthalene and the corresponding 5-halo compounds. The 2-propionic acids are antiinflammatory, analgesic, anti-pyretic and anti-pruritic agents. The 2-propionaldehydes, obtained from the 2-acetyl compounds by way of the 2-propylene oxide, can be converted directly to the 2propionic acids by way of the 2-propionaldoximes and the 2propionitriles or more directly by Jones oxidation. Alternatively the 2-acrylonitriles, obtained from the 2-acetyl compounds by way of the 2-hydroxy-2-propionitrile, can be converted to the 2propionic acid by way of the 2-acrylic acid or 2-propionitrile.

United States Patent [1 Alvarez 1451 Mar. 25, 1975 1 1 2-(6-METHOXYNAPHTH-2-YL) PROPIONITRILE [75] Inventor: Francisco Sanchez Alvarez,

Sunnyvale, Calif.

[73] Assignee: Syntex Corporation, Panama,

Panama [22] Filed: Apr. 26, 1973 [21] Appl. No.: 354,537

Related U.S. Application Data [62] Division of Ser. No. 151,921, June 10, 1971, Pat. No. 1

3,758,544, which is a division of Ser. No. 748,603, July 30, 1968, Pat. No. 3,637,767.

OTHER PUBLICATIONS Sy et a1., Chemical Abstracts, Vol. 68, p. 7523 (1968).

Primary Ermniner-Lewis Gotts Ass/slum! I:'.\'uminurDolph H. Torrence Attorney, Agent, orflrm-Joseph l. Hirsch; William B. Walker [57] ABSTRACT New compounds, 2-(6-methoxynaphth-2- yl)propylene oxide, 2-(6-methoxynaphth-2- yl)propi0naldoximo, -2-hydroxy-2-(6'-methoxynaphth- 2'-yl)propionitrile, 2-(6-methoxynaphth-2- yl)acrylonitri1e, 2-(6-methoxynaphth-2'-yl)acrylic acid, the corresponding 5-halo compounds and 2-(5'- halo 6-methoxynaphth-2-yl)propionaldehyde are useful intermediates in producing 2-(6'- methoxynaphth-2-yl)propionic acid and the corresponding 5-halo acids from 6-methoxy-2- acetylnaphthalene and the corresponding S-halo compounds. The 2-pr0pionic acids are anti-inflammatory, analgesic, anti-pyretic and anti-pruritic agents. The 2- propionaldehydes, obtained from the Z-acetyl compounds by way of the 2-pr0pylene oxide, can be converted directly to the 2-propionic acids by way of the 2-propiona1doximes and the Z-propionitriles or more directly by Jones oxidation. Alternatively the 2-' acrylonitriles, obtained from the 2-acetyl compounds by way of the 2-hydroxy-2-propionitrile, can be converted to the 2-propionic acid by way of the 2-acrylic acid or 2propionitrile.

1 Claim, N0 Drawings 1 2-(6METHOXYNAPHTH-2-YL) PROPIONITRILE This is a division ofapplication Ser. No. 151,921 filed June 10, 1971, now US. Pat. No. 3,758,544, which in turn is a division of application Ser. No. 748,603 filed July 30, 1968, now US. Pat. No. 3,637,767.

It is the object of this invention to provide new com pounds and processes for making them which compounds are useful as intermediates in improved methods for producing 2-(6'-methoxynaphth-2'- yl)pr0pionic acid and the corresponding 5-halo propionicacids.

The compounds, 2-(6'-mothoxynapht h- 2'yl)propionic acid and 2-(5'-halo-6-mothoxynaphth- 2-yl)propionic acid and and the novel intermediates therefor of the present invention can be prepared by processes exemplified as follows, wherein X is halo (fluoro, chloro, bromo or iodo) and Y is hydrogen or no f":

(I l v (vnr) 3 The 2-(6-methoxynaphth-2-yl)propionic acid and corresponding 5 -halo compounds are useful as an antiinflammatory, analgesic, anti-pyrotic and anti-pruritic.

agents as described in US. application Ser. No.

694,771 filed Dec. 7, 1967. The acids can be used in the same manner as aspirin and phenyl butazone.

The preferredmanne r of oral administration provides the use of a convenient daily dosage regimen which can be adjusted according to the degree of affliction. Generally, a daily dose of from 0.1 mg. to mg. of the active compound per kilogram of body weight is employed. Most conditions respond to treatment com-- prising a dosage level in the order of 1 mg. to 5 mg. per

kilogram of body weight per day. For such oral administration, a pharmacoutically acceptable non-toxic I with methanol in the presence of concentrated sulfu-' ric acid at reflux temperatures, for example, 2- methoxynaphthalene is formed. This ether can be separated from the methanol layer of the reaction mixture by conventional means to yield 2-methoxynaphthalene,

- a known compound.

The 2-methoxynaphthalene of Formula II or 2- hydroxynaphthalene of Formula I is halogenated to in troduce a halo group (iodo, bromo, chloro or fluoro) preferably a fluoro, bromo or chloro group at the C-1 position of the naphthalene nucleus. The substitution reaction can be carried out by any conventional technique suitable for the naphthalene system. For example, substitution with iodine, bromine or chlorine can be effected by the procedure described in Ber. 21, 891 (1888). Fluorination can be accomplished by the procedure described in J. Org. Chem. 33, 2469 (1968) replacing estrone with equivalent amounts of 2- bys rqryna zihe safi Preferably, iodation, bromination or chlorination is effected with the halogon in an inert organic solvent,.

reacting the naphthalene compounds with a molecular equivalent of the halogen at temperatures which provide an efficeint, effective reaction. Preferably the reaction is conducted in the presence of a suitable catalyst, although selective halogenation at the C-lposition proceeds very well without a catalyst. Suitable organic solvents include substituted aromatics such as nitrobonzene and halogenated aromatics including monochlorobenzene. the dichlorobenzene, etc.; aliphatic liquid hydrocarbons having at least 8 carbons, chlorinated aliphatic hydrocarbons such as methylene chloride, tetrachloroethylene, carbon tetrachloride, pentachloroethylene, etc.; lower alcohols such as ethanol, butanol, etc.; others havingup to '6 carbons such as diethyl ether; and lower aliphatic carboxylic acid suchas acetic acid, formic acid and the like. The preferred solvents are carboxylic acids such as acetic acid or halogonated hydrocarbons such as methylene chloride, monochlorobenzene, and the like. The elemental halogen is added directly or as a solution with one of the liquid components of the system. The catalysts which promote this reaction are o yentional and well known in I naphthalene the art. Increased yields are often obtained if the reaction is conducted in the presence of lower alphatic carboxylic acids such as formic acid, acotic acid, and the like. The presence of a small quantity of elemental iodine has been found to assist in initiating the reaction. with bromine and chlorine. Iron salts such as ferric chloride also promote the reaction and increase the yield of the a-halo products.

The compounds of Formula IV (wherein X is an iodo, bromo or chloro group) can, alternatively, be produced by first halogenating the 2- hydroxynaphthalene and then forming thhe mothoxy group. The halogenation can be carried out as described above to introduce halo groups, preferably a fluoro, chloroor bromo group at the l-position of the nuclous, yielding the l-halo-2- hydroxynaphthalene of Formula III.

The 2-hydroxy compound of Formula III is then mothylated with dimethyl sulfate in dilute alkali, for example, to form the l-,halo-2-methoxynapthalene of Formula IV.

Of these alternate routes from the compound of Formula I to the compound of Formula IV, the preferred sequence of steps is a first methylation of the Z-hydroxy group followed by halogenation, since this permits the use of simple and more efficient reactions and less expensive reactants.

Fluorination can be accomplished by nitrating 2- hydroxynaphthalene (Formula I) with one eqivalent of nitric acid in an inert organic solvent, to form l-nitro-2- hydroxynaphthalene, reacting this with dimethyl sulfate in dilute alkali to form l-nitro-2- mothoxynaphthalene, hydrogenating the methyl ether over Ranoy nickel, for example, to form l-amino-2- methoxynaphthalene, dia otizing this in aqueous fluoroboric acid to yield the l-diazonium fluoroborate, and thermally decomposing the latter in the presence of copper powder to yield 1-fluoro-2- methoxynaphthalene (Formula IV).

The 6-methoxy-2-acetylnaphthalene and corresponding 5-halo compounds of Formula Vare formed from the 2-methoxynaphthalene of Formula II or l-halo-2-methoxynaphthalene of Formula IV with acetyl chloride or acetic anhydride by a Friedel-Crafts reaction in aninert organic solvent.

When the Z-methoxynaphthalene of Formula II is used as the starting material, the choice of solvent is very important to preferentially form the 6-methoxy-2- acetylnaphthalene. Conducting the reaction in ahitrobenzene solvent system has been found satisfactory. However, nitrobenzene is an expensive solvent, and the yields obtained with it are considerably lower than can be obtained by procedures operable with l-halo-2- methoxynaphthalene starting materials. Separation of the product intermediate from the nitrobenzene is also somewhat difficult.

Therefore, the l-halo-2-methoxynaphthalene of Formula IV is the preferred starting material since high yields of the corresponding. 5-halo-6-methoxy-2- acetylnaphthylene compound of Formula V is obtained in conventional inert organic solvents without the need of a special solvent such as nitrobenzene. In the latter reaction, suitable inert organic solvents include chorinated aliphatic hydrocarbons such as dichloroethylene, methyleno chloride, carbon tetrachlorido, chloroform, totrachloroothylene, and the like.

The preferred catalyst is aluminum trichlorido although other Friedol-Crafts catalysts such as Lewis acids can be used. Examples of suitable catalysts are is conducted at temperatures of from 0100C and, de-' pending upon the temperature, requires up to hours for completion. With an aluminum trichloride catalyst, the reaction is preferably conducted at 0 to 30C for from /2 to 2 hours.

After the product is formed in the reaction mixtures of both of the above processes, the organic layer containing the product is washed, concentrated, and the o-methoxy-2-acetylnaphthalene or its S-halo counterpart is crystallized, washed, recrystallized, washed and dried to provide the acetyl compound of Formula V wherein Y is hydrogen or halogen, depending upon its precursor.

In the above process, 6-methoxy-2- acetylnaphthalene or 5-halo6-methoxy-2- acetylnaphthalene (Formula V) is reacted with dimethylsulfonium methylide or dimethyloxosulfonium methylide in an inert solvent to form the respective 2- (6-methoxynaphth-2'-yl)propylene oxide or 2-( 5'- halo-6-methoxynaphth-2-yl)prop1ene oxide of Formula VI. The dimethylsulfonium or dimethyloxosulfon ium methylide is prepared in situ by mixing trimethylsulfonium or trimethylsulfoxonium halide (chloride, bromide or iodide) with a molar excess (molar ratio greater than 1,1 of a strong base in the solvent system. The acetyl compound (Formula V) dissolved in a solvent is then added.

Trimethlsulfonium halides are known compounds and can be prepared as described by H. J. Emelems et al, J. Chem. Soc. 1126 (1946) and R.-Kuhn et al, Ann. 61 1,1 17 (1958). For example, dimethylsulfide and methyl halide in a suitable solvent can be quantitatively reacted to form trimethylsulfonium iodide which separates as a solid cake. After a suitable time, for example, 24 hours, it can be collected, crystallized from ethanol and washed with ether.

It can also be prepared in situ; methyl halide can be added to dimethylsulfide in a suitable solvent such as dimethylsulfoxide, and the mixture stirred at to C for 4 hours. The mixture, cooled to 10 to 15C, can then be mixed with reactants and solvents according to the above procedure. The preferred halides are the bromide or chloride.

Trimethylsulfoxonium halide is also a known compound and can be prepared by the procedure of R. Kuhn et al, Ann. 611,117 (1958). Diemthylsulfoxide, upon extended refluxing (many days) with a methyl halide such as the chloride, bromide, or iodide forms this reagent. It is used in the same manner as the trimethylsulfonium halide.

As a strong base, alkali metal lower alkoxides such as sodium or potassium methoxide, ethoxide, propoxide, n-butoxide, inobutoxide and t-butoxide (preferably nodium alkoxides) or sodium methylsulfmylmethide can be used. These compounds are all known. The last named compound is formed by reacting powered sodium hydride with excess dimethylsulfoxide and cooling the reaction mixture.

Any conventional inert organic solvent for the reactants can be used. A particularly advantageous solvent is a mixture of dimethylsulfoxide and tetrahydro'furan in a volume ratio of from l-lO:1.

The reaction can be carried out at a temperature of from 0 to 50C and preferably from 10- to 15C until the product is formed. preferably for at least 5 minutes 2-(5'-halo-6-methoxynaphth-2-yl)propylene after addition of the ketone of Formula V to the reaction mixture is complete. The reaction (as well as the preparation of the methylating agent) should be carried out under an inert atmosphere such as nitrogen and the like.

The 2-(6-methoxynaphth-2'-yl)propyylene oxide or 2-(5-halo-6-methoxynaphth-2-yl)propylene oxide can be separated, for example, by diluting the reaction mixture with water and filtering the precipitated propylene oxide from the mixture. It is then preferably washed and dried in preparation for the next step.

The 2-(6'-methoxynaphth-2'-yl)propylene oxide or oxide (Formula VI) can be converted to the 2-(6'- me'thoxynaphth-Z'-yl)propionaldehyde or 2-(5-halo- 6-methoxynaphth-2-yl)propionaldehyde (Forula VII) by several procedures, all of which are indicated by the terms converting. The propylene oxide can be converted to the aldehyde by heating in the absence of a catalyst at a temperature sufficient to effect conversion to the propionaldehyde, that is above 220C, either with or without an inert organic solvent. The propylene oxide, when heated (molted without solvent) at a temperature sufficient to effect the conversion( above C and preferably from 120to C) in the presence ofa Lewis acid forms the aldehyde. In an inert organic solvent system in the presence of a Lewis acid, lower temperatures are effective; for example, the aldehyde is formed at temperatures of from 0 to 30C, preferably from 5 to 10C. The reactions are conducted in an inert atmosphere such as nitrogen.

Examples of suitable Lewis acids include boron trifluoride etherate, boron trifluoride, boron trichloride, aluminum chloride, zinc chloride, stannic chloride, etc., the preferred Lewis acid being boron trifluoride etherate. A particular suitable inert organic solvent is tetrahydrofuran.

The product 2-(6'-methoxynaphth-2'- yl)propionaldehyde or 2-(5'-halo-6-methoxynaphth- 2-yl)propionaldehyde can be separated from the reaction mixture by conventional techniques. Separation is unnecessary, however, since the reaction mixture can be concentrated to a form unable in the next process stop by distillation under reduced pressure, preferably after adding a base such as pyridine.

The 2-(6'-methoxynaphth-2-yl)propionaldehyde or 2-(5-halo-6'-methoxynaphth-2-yl)propionaldehyde or 2-(5'-halo-6'-methoxynaphth-2'- yl)propionaldehyde or 2-(5-halo-6-methoxynaphth- 2-y1)propionaldehyde (Formula VII) can then be reacted with hydroxylamine hydrochloride in an inert solvent to form 2-(6-methoxynaphth-2'- yl)propionaldoxime or- 2-(5'-halo-6-methoxynaphth- 2-yl)propionaldoxime (Formula VIII) according to one process of this invention. The hydroxylamine hydrochloride is a'known reagent. Preferably the reaction medium contains a basic catalyst. A preferred solvent system is a mixture of water and pyridine. The hydroxylamine hydrochloride can be added tothe reaction mixture as an aqueous solution. At least a slight molar excess of hydroxylamine hydrochloride should be used.

The reaction can be carried out at a temperature of from 20 to 100C, the lower temperatures being preferred to decrease side reactions. Since the reaction is exothermic, temperatures of the reacting mixture may each 40C and higher unless cooling is provided. The

reaction is continued until the aldoximo product is formed; since the reaction is very rapid, permitting the reaction mixture to stand for longer than a few minutes is not required.

The aldoxime is then separated from the reaction mixture. For example, the reaction mixture can be diluted with water and extracted with an inert organic, water-immiscible solvent such as methylene chloride, other chlorinated or brominated hydrocarbon liquids, and the like. The preferred solvents are chlorinated solvents such as methylene chloride. The extraction solvent phase [containing the 2-(6'methoxynaphth-2- yl)propionaldoxime or corresponding 5-halo compound] can be concentrated in preparation for the next step. The aldoxime can be separated and purified by crystallization, washing and drying. However, separation is not required, the'extracted concentrate being entirely satisfactory for the next process step.

The 2-(6-methoxynaphth-2'-yl)propionaldoxime or 2-( 5 -halo-6-methoxynaphth-2-yl )propionaldoxime (Formula VIII) is dehydrated by heating at a temperature sufficient to effect dehydration, usually from 100 to 200C and preferably at about 120C or above to form the respective 2-(6-methoxynaphth-2'- y])propionitrile (FormuIa'XI). When the reactionis carried out without solvent or in an inert neutral organic solvent system, the product propionitrile can be separated and purified by conventional techniques. The propionitrile can then be hydrolyzed to the corresponding acid by standard hydrolysis technique with a strong acid or base.

Preferably the dehydration and hydrolysis is carried out in a single step by heating the oxime at temperatures of 100 to 200C, preferably at about 120C or above in a strong alkaline or strong acid medium. For example, the hydrolysis can be conducted in an alcoholic solution of an alkali metal hydroxide to form an alkali metal salt, acidification providing the carboxylic acid.

Suitable alkaline materials for the hydrolysis include sodium hydroxide, potassium hydroxide, and the like, in aqueous solutions of alcohols includingmethanol, ethanol, propanol, isopropanol, t-butanol, ethylene glycol, methoxyethanol, and the like, the higher boiling alcohols being preferred. Hydrolysis is preferably conducted in a potassium hydroxide solution in aqueous ethylene glycol. For the hydrolysis, the reaction mixture is heated until the salt of the product is formed, preferably at 125C.

The reaction mixture is then purified and acidified to form the carboxylic acid which can be separated and purified by conventional techniques. The reaction mixture can be poured into water and extracted with methylene chloride, for example, to remove impurities soluble therein; the aqueous layer can then be diluted with acetone, acidified with a suitable acid such as hydrochloric acid, and heated to distill the acetone from the solution, the carboxylic acid precipitating as the acetone is removed to yield 2-(6-methoxynaphth-2'- yl)propionic acid (Formula XIV) or 2-(5'-halo-6'- methoxynaphth-Z-yl)propionic acid (Formula XII),

depending upon the respective propionaldoxime used.

Alternatively, the hydrolysis (or dehydrationhydrolysis) can be conducted in an aqueous solution of a strong mineral acid such as sulfuric acid, hydrochloric acid, phosphoric acid, and the like, preferably also containing a carboxylic acid having from l3 carbons, the latter being present in concentrations sufficient to increase the solubility of the aldoxime of Formula VIII or nitrile of Formula X1 in the reaction mixture. Heating the aldoxime at to 200 C, preferably at about C or above provides both the dehydration and hydrolysis, yielding the 2-(6-methoxynaphth-2- yl)propionic acid (Formula XIV) or 2-(5'-halo-6- methoxynaphth- 2-yl) propionic acid (Formula XII depending upon whether or not the group at the 5- position is hydrogen or halogen. The product acid can be separated by conventional means.

Alternatively the 2-(6-methoxynaphth-2'- yl)propionaldehyde or 2-(5'-halo-6-methoxynaphth- '2-yl)pr0pionaldehyde of Formula VII can be oxidized directly to the 2-(6-methoxynapth-2-yl)propionic acid (Formula XIV) or 2-(5-halo-6'-methoxynaphth- 2-yl)propionic acid (FormulaXIl), respectively, with a chromic acid solution. This oxidation is carried out in a mixture of acetone and an aqueous solution of chromic acid having a normality of 6 to 10 and preferably about 8, with cooling (reaction temperature of from 20 to 30C, preferably from 5 to 10C. The chromic acid solution can be prepared from water, chromium trioxide and sulfuric acid by known procedures. The propionic acid product can be separated by dilut ing the reaction mixture with water, separating the precipitated solids, and washing and drying them to yield the respective acid.

The presence of the 5'-halo group greatly increases the oxidation yield of the desired propionic acid product over that obtained with the corresponding 5'- hydrogen aldehyde (where Y=Il). The increase in yield is at least 20.percent. Therefore, the preferred reaction procedure throughout this process follows the above diagram wherein Y=X, that is a halo group such as a fluoro, chloro, bromo or iodo group.

The 2-(5'-halo-6-methoxynaphth-2'-yl)propionic acid of Formula XII can be dehalogenated to yield the 2-(6-methoxynaphth-2'-yl)propionic acid of Formula XIV by any conventional dehalogenation procedure which will not disturb the other portions of the compound. A particularly suitable procudure comprises reacting the 5-halo compound of Formula XII (Y=X- =halo) with a mixture of magesium methylate and triethylamine in methanol. For example, a mixture of magnesium powder, methanol, and a molar excess of triethylamine are mixed together, and while maintaining this mixture under an inert atmosphere such as nitrogen, the 2-(5'-halo-6'-methoxynaphth-2'- yl)propionic acid in a methanol solution is added thereto. After the reaction is complete, for example after refluxing for one hour, hydrochloric acid can be added to the reaction mixture to dissolve all remaining magnesium. The propionic acid product (Formula XIV) can be separated by conventional procedures. For example, the reaction mixture can be poured into water and extracted with a suitable solvent such as methylene chloride. The organic layer can then be separated, washed with water, and the 2-(6-methoxynaphth2'-yl)propionic acid (Formula XIV) can be crystallized therefrom.

The 2-(6'-methoxynaphth-2'-yl)propionic acid and its corresponding 5'-halo acids have an asymmotric carbon and are obtained as a mixture of optical isomers. These isomers can be separated by preparing salts of the acids with an alkaloid or similar resolving agent such as cinchonidine, and separating the products by fractional crystallization, the d-acid salt being the least soluble in methanol. The d-salts are acid cleaved to yield the respective optically specific isomers, that is, d-2-(6-methoxynaphth-2-yl)propionic acid or the corresponding d-5'-halo (fluoro, chloro, bromo, or iodo) compounds. Repeating the procedure with an alkaloid which forms a least soluble salt with the respective l-acids provides the pure l-2-(6'- methoxynaphth-2'-yl)propionic acid or the corresponding l-5-halo compounds.

Useful intermediates of this invention for forming 2- (6'-methoxynaphth-2'yl)propionic acid by the procedures described above include 2-(6-methoxynaphth-2'yl)propylene oxide,

2-(5-chloro-6-methoxynaphth-2'-y|)propylene oxide,

2-(5-bromo-6-methoxynaphth-2'-yl)propylene oxide.

2-(5'-iodo6methoxynaphth-2'-yl)propylene oxide,

2-(5-fluoro-6-methoxynaphth-2'-yl)propylene oxide,

2( 6'-methoxynaphth-2 -yl )propionaldoxime.

2-(5'-chloro-6-methoxynaphth-2'- yl)propionaldoxime,

2( 5 '-bromo-6'-methoxynaphth-2'- yl)propionaldoxime,

2-(5-iodo-6'-methoxynaphth-2'- yl)propionaldoxime,

2-(5-fluoro-6-methoxynaphth-2- yl)propionaldoxime, 2-(6'-methoxynaphth-2-yl)propionitrile,

2-( 5 '-chloro-6'-methoxynaphth-2'-yl )propionitrile,

2-( 5 '-bromo-6'-methoxynaphth-2-yl )propionitrile,

2-(5'-iodo-640 -methoxynaphth-2-yl)propionitrile,

2-(5'-fluoro-6'-methoxynaphth-2'-yl)propionitrile,

2-(5'-chloro-6-methoxynaphth-2- yl)propionaldehyde,

2-(5-chloro-6-methoxynaphth-2- yl)propionaldehyde,

2 (5'-iodo-6'-methoxynaphth-2'- yl)propionaldehyde, and

2-(5'-fluoro-6'-methoxynaphth-2- yl)propionaldehyde.

In another alternate procedure of this invention,

6-methoxy-2-acetylnaphthalene or 5-halo-6- methoxy-2-acetylnaphthalene (Formula V) is reacted with diethylaluminum cyanide in an inert solvent to form 2-hydroxy-2-(6'-methoxynaphth-2- yl)propionitrile or 2hydroxy-2-(5'-halo6'- methoxynapthth-Z-yl)propionitrile, respectively, of Formula lX.

Diothylaluminum cyanide is a known reagent which can be made by reacting triethylaluminum with hydrogen cyanide in a hydrocarbon solvent such as benzene.

The reaction with diathylaluminum cyanide is carried out in an anhydrous solvent system, for example with a hydrocarbon solvent such an a mixture of toluene and benzene. The reaction can be carried out at temperatures of from 50 to 30C. The best yield is obtained at the lower temperatures, such as from 40 to 10C. The reaction is continued until the product is formed, usually for at least 5 minutes, and preferably for longer thhan 10 minutes. The than of course, will depend upon the reaction conditions, the lower temperatures requiring longer reaction times.

The propionitrile is then separated from the reaction mixture. For example, the reaction mixture can be neutralized by mixing it with an aqueous alkali metal hydroxide solution, and the 2-hydroxy-2-(6- methoxynaphth-Z -yl )propionitrile or corresponding to form the 2-(6-methoxynaphth2-yl)acrylonitrile or 2-( 5 -halo-6 -methoxynaphth-2 '-yl )acrylonitrile of Formula X. This dehydration can be accomplished with any conventional dehydrating reagent. Examples of suitable reagents aresulfuric acid, formic acid. acetic anhydride, phosphorus oxichloride, potassium bisulfate (potassium hydrogen sulfate), phosphorus pentoxide, activated alumina, anhydrous potassium carbonate, thionyl chloride, aluminum powder and the like.

The preferred dehydrating agent is potassium bisulfate, and a suitable procedure for using this reagent comprises intimately mixing the cyanohydrin of Formula [X with freshly fused and powdered potassium bisulfate, preferably with a small quantity of hydroquihone, and distilling the acrylonitrile of Formula X from the reaction mixture. The acrylonitrile can be recovered by drying and redistilling the original distillate to yield 2-(6'-methoxynaphth-2'-yl)-acrylonitrile or 2- (5-halo-6-methoxynaphth-2-yl)acrylonitrile, depending upon whether the parent cyanohydrin has hydrogen or a halo group at the C-5 position. The temperature conditions for the dehydration reaction will depend upon the particular catalyst used and are known in the art. Depending upon the particular catalyst, the reaction temperature can be within the range of from 0 to 200C, for example. Using potassium bisulfate, reaction temperatures of from l00 to 200C and preferably from to C are employed. The

reaction time will also depend upon the technique used; with potassium bisulfate, the reaction mixture is heated until vapor evolution is complete.

Alternate procedures can be used for deriving the 2- (6-methoxynaphth-2-yl)propionic acid of Formula XIV from the 2-(6'-methoxynaphth-2-yl)acrylonitrile or 2(5'-halo-6'-methoxynaphth-2-yl)acrylonitrile of Formula X. In one procedure, the acrylonitrile of Formula X is first hydrogenated to form the 2-(6'- methoxynaphth-2'-yl)propionitrile of Formula XI which is then hydrolyzed to form the propionic acid of Formula XIV.

Catalyic hydrogenation is carried out in an inert solvent using conventional catalysts and procedures. Hydrogenation using platinum oxide catalysts or palladium-on-carbon catalysts has the advantage of room temperature and low pressure operating conditions. Other conventional catalysts such as nickel-on-Kiesolguhr or Raney nickel catalysts can be used but they require higher pressures and temperatures of from 25 'to 250C. Simultaneous dehydration and hydrogenation of the cyanohydrin of Formula [X to the propionitrile of Formula X] can also be accomplished with a catalyst such an activated alumina and nickel oxide. In these precedures, the hydrogen is usually bubbled through a solution of the acrylonitrile in an inert organic solvent such as methanol, other lower alcohol, or the like, the solution containing the suspension of the particular catalyst. The product propionitrile is then separated from the reaction mixture. For example, the catalyst can be separated from the reaction mixture, and the product can be then crystallized from the solution. Chloro, bromo and iodo groups at the 5-position of the naphthalene nucleus are simultaneously replaced with hydrogen using many of the above catalyst systems. In catalytic systems where 5'-halo groups (for example the fluoro group) remain on the hydrogenated product, they can be removed using magnesium methylate and triethylamine in methanol by the procedure described above.

Hydrolysis of the propionitrile of Formula Xl can be accomplished using either of the above-described acid or alkalino procedures to form the 2-(6'- methoxynaphth-Z-yl)-propionic acid of Formula XIV.

Alternatively, the acrylonitrile of Formula X is first hydrolyzed by one of the above-described procedures to form the 2-(6-methoxynaphth-2yl)acrylic acid or 2-(5-halo-6-methoxynaphth-2-y|)acrylic acid of Formula Xlll which is then catalytically hydrogenated to form the product 2-(6-methoxynaphth-2"yl)propionic acid of Formula XlV by one of the procedures described above. Dehalogenation of chloro, bromo and iodo groups, as noted above, usually accompanies hydrogenation, but if the halo group remains upon the naphthalene nucleus, it can be removed, for example, by the magnesium methylatetriethylamine procedure described above.

Examples of intermediate compoundsof thin invention which are useful in the above alternate process include 2-hydroxy-2-(6-methoxynaphth-2yl)propionitrile,

2-hydroxy-2-(5'-chloro-6-methoxynaphth-2 -yl)propionitrile, 2-hydroxy-2-(5-bromo-6-methoxynaphth-2- yl)propionitrile, 2-hydroxy-2-(5-iodo-6-methoxynaphth-2'- yl)propionitrile, 2-hydroxy-2-(5'-fluoro-6'-methoxynaphth-2'- yl)propionitrile,

2-(6'-methoxynaphth-2-yl)acrylenitrile,

2-( 5 -chloro-6-methoxynaphth-2'-yl)acrylenitrile,

2-(5-bromo-6-methoxynaphth-2-yl)acrylenitrile,

2-(5'-iodo-6-methoxynaphth-2'-yl)acrylenitrile, v

2-(5'-fluoro-6'-methoxynaphth-2-yl)acrylenitrile,

2-(6-methoxynaphth-2-yl)acrylic acid,

2-(5'-chloro-6-methoxynaphth-2'-yl )acrylic acid,

2-(5-bromo6methoxynaphth-2-yl)acrylic acid,

2-(5-fluoro-6'-methoxynaphth-2-yl)acrylic acid,

and

2-(6-methoxynaphth-2-yl)propionitrile.

The invention is further illustrated by the following specific but non-limiting examples.

EXAMPLE 1 A stirred solution of 2-methoxynaphthalene (5 g.) in acetic acid 100 ml.) is treated dropwise with a solution of LI molar equivalents of bromine in acetic acid (50 ml.). Upon disappearance of the bromine color, water is added. The solid which forms is collected by filtration, washed with water until neutral, recrystallized, rewashed, and dried to yield l-bromo-Z- methoxynaphthalene.

EXAMPLE 2 Repeating the procedure of Example 1 but replacing bromine with 1.] moles of chlorine (bubbled through the reaction mixture) or 1.1 moles of iodine (in 50 ml. of acetic acid) yields l-chloro-2-methoxynaphthalene or l-iodo-2-methoxynaphthalene, respectively.

EXAMPLE 3 Lhydroxynaphthalene (l g.) is dissolved in boiling acetic acid (30 ml.), and when the solution temperature reaches 45C. a molecular equivalent amount of concentrated nitric acid is slowly added. After standing overnight at room temperature, the reaction mixture is mixed with water, The procipitated solids are filtered, 5 washed with water, and purified by chromatography on alumina, to yield l-nitro-l-hydroxynaphthalene.

l-nitro-2-hydroxynaphthalene (0.5 g.) is methylated with a molar excess of dimethyl sulfate in tetrahydrofuran (50 ml.) and lOpercent potassium hydroxide solution (50 ml.) over a period OH) to 8 hours with periodic addition ofa 40 percent potassium hydroxide solution (32 ml.) to maintain basicity of the reaction mixture. The l-nitro-2-methoxynaphthalene product is separated from the reaction mixture, washed and dried.

l-nitro-2-methoxynaphthalene l g.) is hydrogenated in absolute ethanol (200 ml.) over Raney nickel catalyst (l g.) at 25 C. and an initial pressure of 4 psi until the theoretical amount of hydroge n is absorbed. The catalyst is removed, the filtrate concentrated to dryness under vacuum, and the residue recrystallized from methanol to yield l-amino-2- methoxynaphthalene.

A suspension of l-amino-2-methoxynaphthalene (l g.) in a mixture of tetrahydrofuran (50 ml.), dioxane (l ml.) and 48 percent aqueous fluoroboric acid (12.5 ml.) is chilled to 0C. A solution of sodium nitrate (6.2 g.) in cold water (20 ml.) is added dropwise over minutes to the vigorously stirred mixture while maintaining the temperature at 0 to 10C. The slurry is stirred for one hour at 0C and diluted with cold Water (650 ml.), precipitating the l-diazonium fluoroborate of 2- methoxynaphthalene. The precipitate is separated, washed with either and dried.

' A mixture of the diazonium fluoroborate (l g.) and copper powder (1 g.) is spread in a thin layer in a sublimation apparatus and decomposed under vacuum (0.2

mm.) by increasing the oil bath temperature slowly to 170C over a period of 6 hours. The solid material which had sublimed onto the sides of the still is collected, dissolved in chloroform, filtered, dried. and chromatographed on acid-washed alumina, eluting with benzene to yield l-fluoro-2-methoxynaphthalene.

EXAMPLE 4 Repeating the procedures of Examples 1 and 2 but replacing 2-methoxynaphthalene with 2- hydroxynaphthalene yields l-bromo-Z- hydroxynaphthalene, l-choro-2-hydroxynaphthalene and l-iodo-2-hydroxynaphthalene, respectively.

' EXAMPLE 5 In N sodium hydroxide (100 ml.), l-chloro-2- hydroxynaphthalene is dissolved, and the solution is filtered and cooled. Dimethyl sulfate 10 ml.) is added to the solution, and the product precipitates from the reaction mixture after a few minutes. The solids are broken up and washed with l N sodium hydroxide (100 ml.). The solids are dried azeotropically with benzene followed by distillation to yield l-chloro-2- methoxynaphthalene.

Repeating this procedure with 1-bromo-2- hydroxynaphthalene or 1-iodo-2-hydroxynaphthalene yields l-bromo-2-methoxynaphthalene or l-iodo-2- methoxynaphthalene, respectively.

EXAMPLE 6 By the following procedure, 6-methoxy-2- acetylnaphthalene was produced. Nitrobenzene (14,000 ml.) and B-naphthol methyl ether (2000 g.)

were mixed under nitrogeh and cooled to to C.-To

. this solution was added aluminum trichloride (2600 g.)

in nitrohenzcne (20,000 ml.) procooled to 0 pre cooled 5C. Acetyl chloride l 300 g.) was added to this mixture over a period of 30 to 40 minutes while maintaining the temperature below 25C. After addition of the acetyl chloride was complete, the mixture was heated to 35C and maintained at that temperature for hours.

The reaction mixture was repeatedly washed with water containing hydrochloric acid to remove organic impurities from the nitrobenzene layer, and the nitrobenzene layer was concentrated under vacuum to a heavy syrup. The 6-methoxy-2-acetylnaphthalene product was precipitated by adding methanol and then water, filtered, washed, dried, and crystallized from cyclohexane.

Repeating this procedure but replacing the nitrobenzene with dichloromethylene and replacing the ,B-naphthol methyl ether with l-bromo-2- methoxynaphthalene, lchloro-2- methoxynaphthalene, and l-fluoro-2- methoxynaphthalene5 acetylnaphthalene, acetylnaphthalene,

-bromo-6-methoxy-2- 5-chloro-6-methoxy-2- and 5-fluoro-6-methoxy-2- .acetylnaphthalene, respectively, were produced. A

higher yield was obtained starting with the halo compounds, and less extensive processing was required to obtain a product having high purity.

EXAMPLE 7 A mixture of dimethyl sulfoxide (4800 ml.) and tetrahydrofuran (400 ml.) was purged with nitrogen and cooled to 10 to C. To this mixture was added sodium mcthoxidc (500 g.) and trimethylsulfonium io was added over a period of 30 minutes. After maintaining the temperature of the mixture at from 10 to 15C (5-chloro-6'-methoxynaphth-2-yl)propylene for another 15 minutes, the reaction mixture was diacetylnaphthalene with 5-bromo-6-methoxy-2- acetylnaphthalene, 5-chloro-6.-methoxy-2- acetylnaphthalene Y and 5-fluoro-6-methoxy-2- acetylnaphthalene 2-(5-bromo-6'-methoxynaphth2-yl)propylene oxide, 2-(5-fluoro-6- methoxynaphth-2-yl)-propylene oxide, respectively,

were obtained.

The trimethylsulfonium iodide used in this example was prepared by slowly adding dimethyl sulfide (2000 g.) to methyl iodide (4660 g.) while cooling in an ice bath. The mixture was left at 20C overnight, and the solid reaction cake was recrystallized from hot water, dried at 15C, and stored in a desiccator until used.

EXAMPLE 8 A mixture of tetrahydrofuran (7000 ml.) and 2-(6- methoxynaphth-2-yl)propylene oxide (1060 g.) was purged with nitrogen and cooled to 5to 10C. During a period of 15 minutes, a solution of boron trifluoride etherate (4 ml.,): in tetrahydrofuuran (1200 ml.) was ynaphth2 '-yl )propionic vfluoro-6'-methoxynaphth-2-yl )propionaldoxime,

added with stirring to the mixture. After the addition was complete, the mixture was stirred for 30 minutes at 5 to 10C. Pyridine (8 ml.) was added to the reaction mixture, and the resultant mixture was concontrated to 2000 ml. by distillation under reduced pressure. This concentrate contained 2-(6- methoxynaphth-Z'-yl)propionaldehyde.

Repeating this procedure but replacing the 2-(6'- methoxynaphth-2-yl)propylene oxide with 2(5'- bromo-6-methoxynaphth 2'-yl)propylene oxide, 2-

oxide. and 2-(5-fluoro-6"'methoXynaphth-Z-yl)propylene oxide 2-(5'-bromo 6'-methoxynaphth2'- yl )propionaldehyde, 2-( 5 -chloro-6'-methoxynaphth- 2-yl )propionaldehyde, and 2-(5 '-fluoro- 6- methoxynaphth-2'-yl)propionaldehyde, respectively, are obtained.

EXAMPLE 9 The residue containing 2-(6-mmethoxynaphth-2 yl)propionaldehyde from the procedure of Example 8 was used as produced. To the residue was added pyridine (6500 ml.) and distillation was continued at reduced pressure until the liquid temperature began to rise drastically, indicating the absence of residual tetrahydrofuran. To this was added a solution of hydroxylamine hydrochloride (400 g.) in water (800 ml.), and the mixture was heated in a stirred bath for 15 minutes. The mixture was then cooled, and water (5000 ml.) and methylene chloride (400 ml.) were added. The mixture was stirred vigorously, and the phases were permitted to separate. The lower organic phase was separated, and the aqueous phase was extracted with methylene chloride. The organic phases containing the 2-(6-methoxynaphth-2'-yl)propionaldoxime were concentrated to 1500 to 2000 ml. by distillation, first at atmospheric pressure and the under vacuum.

Repeating the above procedure but replacing the 2- (6-methoxynaphth-2-yl)propionaldehyde with 2-(5- bromo6'-methoxynaphth-2-yl)propionaldehyde, 2- (5-chloro-6-methoxynaphth-2-yl)propionaldehyde, and 2-(5-fluoro-6'-methoxynaphth-2'- yl)propionaldehyde 2-(5-bromo-6'- methoxynaphth-2--yl)propionaldoxime, 2-(5'-chlor0- 6-methoxynaphth-2-yl)propionaldoxime, and 2-(5'- spectively, are obtained in a concentrated solution.

EXAMPLE 10 Each of the crude residues from the procedure of Example 9 was used in the form produced. To each of these residues was added ethylene glycol (7200 ml.) and a solution of potassium hydroxide g.) in water (100 ml.). With gentle stirring, the mixtures were heated to a temperature of about C and maintained at this temperature for 7 hours. The reaction mixtures each were cooled and poured into water (60,000 ml), and each of the mixtures was extracted with methylene chloride, the extracts being discarded.

The aqueous layers, diluted with acetone (20,.000 ml.) were warmed to 45 to 50C, and the warmed mixtures were slowly acidified with concentrated hydrochloric acid (750 ml.). The acetone was largely removed by distillation under vacuum, and the resultant suspensions were cooled to 15C, filtered and washed,

with water. The damp cakes of 2-(6'-methoxynaphth- 2-yl)propionic acid, 2-(5'-bromo-6'-methoxacid, 2-(5-chloro-6- methoxynaphth-2 -yl )propionitrile,

mcthoxynaphth-2'-yl)propionic acid, and 2(5;fluoro- 6methoxynaphth-2'-y|)-propionic acid. respectively, were redissolved .in acetone, treated with charcoal, filtered, concentrated, and reprecipitated with water.

The filtered materials were washed with water and dried. The products were mixtures of d-and l-isomers of the respective acids.

EXAMPLE 11 EXAMPLE 12 One mole of 6 -methoxy-2-acetylnaphthalene is added to a mixture of anhydrous benzene (32 ml.) and anhydrous toluene (19 ml.), and the solution is cooled to C. To this is added 2.3 moles of diethylaluminum cyanide prepared by the procedure of Exam ple 1 1. After minutes, the reaction mixture is poured into a stirred mixture of sodium hydroxide (20 g.) and water (500 ml.), and this mixture is extracted with chloroform. The organic layer is purified and evaporated, and the residue is recrystallized from chloroform. The product is 2-hydroxy-2-( 6- methoxynaphth 2-yl)propionitrile.

Repeating the procedure but replacing the 6-methoxy2-acetylnaphthalene' with 5-bromo-6 methoxy-Z-acetylnaphthalene, 5-chloro-6-methoxy-2- acetylnaphthalene, and 5-fluoro-6-methoxy-2- acetylnaphthalene 2-hydroxy-2-(5'-bromo-6- 2-hydroxy-2-(5- and 2- chloro6 -methoxynaphth-2 -yl )propionitrile,

yl)propionitrile, respectively, are obtained.

EXAMPLE 13 EXAMPLE 14 A quantity of 2-(6'-methoxynaphth-2'- yl)acrylonitrile produced by the procedure of Example 13 (100 g.) is added to a mixture of ethylene glycol (700 ml.) and a solution of potassium hydroxide (100 g.) in water 100 ml.). With gentle stirring, the mixture is heated to a temperature of about 125C and maintained at this temperature for 7 hours. The reaction mixture is cooled and poured into water (6000 ml.). and the mixture is extracted with methylene chloride. the extracts being discarded.

The aqueous layer, diluted with acetone (2000 ml.), is warmed to 45 to 50C, and the warmed mixture is slowly acidified with concentrated hydrochloric acid ml.). The acetone is largely removed by vacuum distillationvand the resultant suspension is cooled to 15C, filtered and washed with water. The damp cake of 2-(6-methoxynaphth-2-yl)acrylic acid is redissolved in acetone, treated with charcoal, filtered, concentrated and reprocipitated with water. The filtered materials were washed with water and dried.

Repeating this procedure but replacing the 2-(6'- methoxynaphth-Z-yl)acrylonitrile with 2-(5-bromo- 6-methoxynaphth-2-yl)acrylonitrile, 2-(5'-chloro-6- methoxynaphth-2'-yl)acrylonitrile, and 2-(5-fluoro- 6-methoxynaphth-2-yl)acrylonitrile 2-(5'-bromo- 6-methoxynaphth-2'-yl)acrylic acid, 2-(5-chloro-6- methoxynaphth-Z-yl)acrylic acid, and 2-(5-fluoro-6- methoxynaphth-2'-yl)acrylic acid, respectively are obtained.

EXAMPLE 15 'methOXynaphth-Z-yl)acrylic acid d1-2-(6'- methoxynaphth-Z-yl)propioni'c acid is obtained. Repeating the procedure with 2-(5'-fluoro-6- methoxynaphth-Z-yl)acrylic acid yields 2-(5-fluoro- 6'-methoxynaphth-2-yl)propionic acid.

EXAMPLE 16 Following the hydrogenation procedure of Example 15 but replacing the 2-(6-methoxynaphth-2-yl)acrylic acid with 2-(6-methoxynaphth-2-yl)acrylenitrile, 2- (5'-bromo6-methoxynaphth-2-yl)acrylonitrile and 2-(5-chloro-6'-methoxynaphth-2-yl)acrlonitrile 2-(6'-methoxynaphth2'-yl)propionitrile is obtained in each instance. Repeating the procedure with 2-(5'- fluoro-6'-methoxynaphth-2-yl)acrylonitrile yields 2- (5-fluoro-6-methoxynaphth-2'-yl)propionitrile.

EXAMPLE 17 Following the hydrolysis procedure of Example 14 but replacing 2-(6-methoxynaphth-2-yl)acrylonitrile with 2-(6-methoxynaphth-2-yl)propionitrile or 2-(5'- fluor06'-methoxynaphth-2-yl)propionitrile d1-2- (6-methoxynaphth-2'-yl)propionic acid or 2-(5- fluoro-6-methoxynaphth-2yl)propionic acid, respectively, is formed.

EXAMPLE 18 A solution of 8 N chromic acid (prepared by mixing 26 g. of chromium trioxide with 23 ml. of concentrated sulfuric acid and diluting with water to I ml.) is added, under nitrogen, to a stirred solution of l g. of 2-(5'-bromo-fi'-methoxynaphth-2'-yl)propionaldehyde in H) ml. of acetone which has been cooled to 0C, addition of the chromic acid is continued until the color of the reagent persiuts in the mixture. The mixtureis then stirred for 5 minutes at O to 5C and diluted with water. The solid which forms is collected by filtration, washed with water and dried under vacuum to yield d I 2-(5 -bromo-6'-methoxynaphth-2-yl)propionic acid.

Repeating the procedure with 2-(5-chloro-6'- methoxynaphth-2'-yl)propionaldehyde, 2-(5'-fluoro- 6-methoxynaphth2-yl)propionaldehyde, and 2-(6- methoxynaphth-2'-yl)propionaldehyde yields dl-2(5- chloro-6'-methoxynaphth2-yl)propionic acid, dl-2- (5'-fluoro-6' methoxynaphth2'-yl)propionic acid, and d1-2-(6-methoxynaphth-2-yl)propionic acid, respectively.

The presence of the 5'-halo group, however, greatly increases the yield of the final product, the respective yields being at least 85 to 95 percent from the 5'-halo compounds in contrast to only 75 to 85 percent from the corresponding unhalogenated aldehyde.

EXAMPLE 19 To a 250 ml. flask equipped with a reflux condenser having a nitrogen huhbler was added magnesium powder (60 g), anhydrous methanol (50 ml. and triethylamine (ll) g.). The flask was swept withnitrogen, and a nitrogen atmosphere was maintained throughout the reaction period. From a dropping funnel was slowly added dl-2-(5'-bromo-6'-methoxynaphth-2'- yllpropionic acid (0.1 molo) in methanol (15.0 g.). The mixture was heated under reflux for 1 additional hour after the 2-(5'-bromo-6--methoxynaphth-2'- yl)propionic acid addition was complete. The cooled mixture was mixed with 6 N hydrochloric acid until no magnesium remained. The mixture was poured into water, methylene chloride was added, and the mixture was 18 shaken. The organic layer was separated, washed with water, and the d1-2-(6'-methoxynaphth-2'- yl)propionic acid product was crystallized by concontrating the solution and adding hexene.

This procedure, repeated with dl-2-(5-fluoro-6-- methoxynaphth-2-yl)propionic acid, and dl-2-(5'- iodo6-methoxynaphth-2-yl)propionic acid also yielded dl-2-(6'-methoxynaphth-2 yl)propionic acid in each instance.

EXAMPLE 20 In separating the mixture of dand lisomers formed by the procedures of Examples l0, l5, l7, and 18, d1- 2-(6-methoxynaphth-2'-yl)propionic acid was added to a methanol solution of cinchonidine; and the cin- 'chonidine salt of the d-acid was crystallized from the solution; this salt was recrystallized from a solution of acetone and methanol and then recrystallized from a solution of pyridine and isopropanol, the product was hydrolyzed with hydrochloric acid and extracted with ethyl acetate. The extract was mixed with isopropanol. 'and the mixture was distilled to remove ethyl accetate and precipitate the product. The precipitate was washed with cool isopropanol and dried to provide d-2- (6-methoxynaphth-2'-yl)propionic acid having a melting point of l55.3C and an opical rotation of [alD=65.5 (C 1.0 in CHCl Repeating this procedure with dl-2-(o-methoxynaphth2'-yl)propionic acids having a halo group at position C(fluoro, chloro, bromo or iodo). the respective d-5'-halo compound is obtained, e.g. d-2-(5'- fluoro-6-methoxynaphth2-yl)propionic acid, d-2-(5'- chloro-6- methoxynaphth-2-yl)propionic acid, d-2- (5'-bromo-6-methoxynaphth-2-yl)propionic acid,

1. 2-(6-methoxynaphth-2-yl)propionitrile.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,873,594 Dated March 25, 1975 I ve i-( Francisco Sanchez Alvarez (Page 3 of 3) It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 14, line 20, "mmethoxynaphth-" should read methoxynaphth- Column 14, line 30, "(400 ml.) should read (4000 ml.) Column 14, line 40, "bromo6"" should read bromo6' Column 15, line 15, "season" should read ceases Column 15, line 37, "chloro6'-" should read chloro-6' Column 15, line 49, "other." should read ether. Column 15, line 50, 'other" should read ether Column 15, line 55, "hydroxy2" should read hydroxy-Z- Column 15, line 60, "acrylonoitrile" should read acrylonitrile Column 16, line 14, "reprocipitated" should read reprecipitated Column 16, line 48, "acrylenitrile, should read acrylonitrile, Column 16, line 49, "bromo6'" should read bromo6' Column 16, line 50, "acrlonitrile" should read acrylonitrile Column 16, line 51, "methoxynaphth2'" should read methoxynaphth2' Column 16, line 60, "fluoro6'-" should read fluoro6'- Column 17, line 6, "persiuts" should read persists Column 17, line 13, "methoxynaphth2'-" should read methoxynaphth2' Column 17, line 15, "methoxynaphth2'" should read methoxynaphth-2' Column 17, line 16, "methoxynaphth2'" should read methoxynaphth2'- Column 17, line 33, (0. l molo) should read (0 .1 mole) Column 18, line 3, "concon" should read concen- Column 18, line 5, after "with" insert dl-2-(5'chloro6methoxynapth-Z'- yl)propionic acid, Column 18, line 7, "iodo6'" should read iodo6' Column 18, line 27, "D=65.5" should read D=+65.5 Column 18, line 29, "ynaphth2'" should read ynaphth2'- Column 18, line 30, "C(fluoro," should read C-5' (fluoro, Column 18, line 32, "methoxynaphth2'" should read methoxynaphth2' Signed and Scaled this fourth D 3} 0f November 1975 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN' Arresting Officer Commissioner ojlatems and Trademark: 

1. 2-(6''-METHOXYNAPHTH-2-YL)PROPIONITRILE. 